X-linked hypophosphatemia (vitamin D-resistant rickets) is caused by mutant dominant genes on the X chromosome of humans (HYP; HPDR) and mice (Hyp). One principal defect is the impaired renal tubular reabsorption of phosphate which leads to increased urinary loss of phosphate, reduced plasma phosphate and hypophosphatemic bone disease in both species. In addition, the activation of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D is not stimulated, and the failure of plasma 1,25-dihydroxyvitamin D to increase is a significant pathogenic feature of this disease. Results from the cross-circulation of blood by parabiosis between normal and Hyp mice suggest that the Hyp mice produce a humoral factor which lowers the renal retention of phosphate and blocks the increase in 1,25-dihydroxyvitamin D synthesis. Further pilot data suggest the presence of an inhibitor to the activity of IGF-1 (insulin-like growth factor; somatomedin) in the serum of the Hyp mice. This inhibitor may be a significant pathogenic factor by contributing to the renal defects in X-linked hypophosphatemia. The prime objective of this proposal is to rigorously test the hypothesis that n IGF- 1 inhibitor exists in the serum of Hyp mice. Four experiments will be done: (1) Measurements will be made of the levels of IGF-1 activity in the serum of normal and Hyp mice by the more sensitive assay utilizing costal cartilage of hypophysectomized rats. This will confirm the presence of reduced IGF-1 activity in the sera of the Hyp mice. (2) Hyp and normal mouse sera will be fractionated by size exclusion chromatography to separate IGF-1 from its inhibitor. This will permit separate measurement of IGF-1 and its inhibitor in the sera and will provide direct data for the presence of an inhibitor. In addition, the approximate molecular size of the inhibitor will be determined. (3) An assessment will be made as to whether this inhibitor has the same physiological regulation by glucocorticoids as previously studied IGF-1 inhibitors. (4) Hyp mice will be treated with 1.25-dihydroxyvitamin D or increased dietary calcium and phosphate to restore skeletal growth. Serum levels of IGF-1 and its inhibitor will be measured to determine if improved bone growth is associated with a decrease in the levels of the IGF-1 inhibitor. Through improved knowledge of the mechanism of the disease process in X-linked hypophosphatemia will come the potential for novel therapies. This will permit better treatment of the human disease and improve the quality of life for patients with this common metabolic disorder.